A decline in physical health decreases quality of life and increases mortality rate for individuals with mental illness. The mind-body pathway(s) by which psychopathologies affect whole body health, e.g.,contribute to the development of metabolic and cardiovascular disease, are unclear. Altered cytokine production is present in depression, post-traumatic stress disorder (PTSD) and chronic stress, and represents a potential pathway by which the brain could affect physical health. The overall research objective of the applicant is to provide a mechanistic explanation of the interrelations between brain, stress and cytokine regulation. The research objective of this proposal is to examine a potential pathway by which the brain could control the cytokine response to acute stressors, i.e., cytokine release from the hypothalamo-neurohypophysial system (HNS). IL-1beta and IL-6, cytokines implicated in disease progression, are expressed in the magnocellular neurons of the supraoptic and paraventricular nuclei and stored in the posterior pituitary. Although IL-1beta and IL-6are positioned to be secreted into the general circulation under the control of the hypothalamic neurons, it is not known if this stored cytokine pool can be recruited to affect blood cytokine concentrations. This proposal is designed to test the hypothesis that the cytokine response to acute stressors is controlled by cytokine-producing neurons in HNS. Two aims are proposed to accomplish the objective of this proposal: 1) Aim 1 will test the hypothesis that the HNS is necessary for the cytokine response to psychological stress;and 2) Aim 2 will test the hypothesis that the cytokine positive neurons of the SON and PVN are stress responsive. The completion of these studies will demonstrate whether the HNS controls the cytokine response to pyschological stress and will determine the effect of stress on cytokine expression in theHNS. Singnificance: There is a increase in the inflammatory state in individuals with mental illness that is thought to play a role in disease progression. Brain control pathways are thought to affect the inflammatory state but are not clearly established. This research proposal tests a mechanism of brain control of inflammation.